Levosimendan for resuscitating the microcirculation in patients with septic shock: A randomized controlled study

__Introduction:__ The purpose of the present study was to investigate microcirculatory blood flow in patients with septic shock treated with levosimendan as compared to an active comparator drug (i.e. dobutamine). The primary end point was a difference of ≥ 20% in the microvascular flow index of small vessels (MFIs) among groups. __Methods:__ The study was designed as a prospective, randomized, double-blind clinical trial and performed in a multidisciplinary intensive care unit. After achieving normovolemia and a mean arterial pressure of at least 65 mmHg, 40 septic shock patients were randomized to receive either levosimendan 0.2 μg·kg-1·min-1(n = 20) or an active comparator (dobutamine 5 μg·kg-1·min-1; control; n = 20) for 24 hours. Sublingual microcirculatory blood flow of small and medium vessels was assessed by sidestream dark-field imaging. Microcirculatory variables and data from right heart catheterization were obtained at baseline and 24 hours after randomization. Baseline and demographic data were compared by means of Mann-Whitney rank sum test or chi-square test, as appropriate. Microvascular and hemodynamic variables were analyzed using the Mann-Whitney rank sum test. __Results:__ Microcirculatory flow indices of small and medium vessels increased over time and were significantly higher in the levosimendan group as compared to the control group; P = .02; MFIs 2.9. The relative increase of perfused vessel density vs. baseline was significantly higher in the levosimendan group than in the control group. In addition, the heterogeneity index decreased only in the levosimendan group. There was no statistically significant correlation between systemic and microcirculatory flow variables within each group. __Conclusions:__ Compared to a standard dose of 5 μg·kg-1·min-1of dobutamine, levosimendan at 0.2 μg·kg-1·min-1improved sublingual microcirculatory blood flow in patients with septic shock, as reflected by changes in microcirculatory flow indices of small and medium vessels.Trial registration: NCT00800306

Activation of Regulatory T Cells during Inflammatory Response Is Not an Exclusive Property of Stem Cells

BACKGROUND: Sepsis and systemic-inflammatory-response-syndrome (SIRS) remain major causes for fatalities on intensive care units despite up-to-date therapy. It is well accepted that stem cells have immunomodulatory properties during inflammation and sepsis, including the activation of regulatory T cells and the attenuation of distant organ damage. Evidence from recent work suggests that these properties may not be exclusively attributed to stem cells. This study was designed to evaluate the immunomodulatory potency of cellular treatment during acute inflammation in a model of sublethal endotoxemia and to investigate the hypothesis that immunomodulations by cellular treatment during inflammatory response is not stem cell specific. METHODOLOGY/PRINCIPAL FINDINGS: Endotoxemia was induced via intra-peritoneal injection of lipopolysaccharide (LPS) in wild type mice (C3H/HeN). Mice were treated with either vital or homogenized amniotic fluid stem cells (AFS) and sacrificed for specimen collection 24 h after LPS injection. Endpoints were plasma cytokine levels (BD™ Cytometric Bead Arrays), T cell subpopulations (flow-cytometry) and pulmonary neutrophil influx (immunohistochemistry). To define stem cell specific effects, treatment with either vital or homogenized human-embryonic-kidney-cells (HEK) was investigated in a second subset of experiments. Mice treated with homogenized AFS cells showed significantly increased percentages of regulatory T cells and Interleukin-2 as well as decreased amounts of pulmonary neutrophils compared to saline-treated controls. These results could be reproduced in mice treated with vital HEK cells. No further differences were observed between plasma cytokine levels of endotoxemic mice. CONCLUSIONS/SIGNIFICANCE: The results revealed that both AFS and HEK cells modulate cellular immune response and distant organ damage during sublethal endotoxemia. The observed effects support the hypothesis, that immunomodulations are not exclusive attributes of stem cells

Absorption pharmacokinetics of clonidine nasal drops in children

Background: The α2 agonist clonidine has become a popular drug for premedication in children. Effects and pharmacokinetics after oral, rectal, and intravenous administration are well known. The aim of this study was to investigate the absorption pharmacokinetics of clonidine nasal drops in children. Methods: Thirteen ASA I pediatric patients received after induction of anesthesia 4 mcg·kg -1 of clonidine by the nasal route. Blood samples were taken during a 12-h period and plasma levels of clonidine were analyzed by liquid chromatography-mass spectrometry. Data were calculated by a computer-aided curve-fitting program. Results: Plasma pharmacokinetics following administration of clonidine nasal drops showed a considerable interindividual variability and absorption was delayed and limited. A total of 95% confidence intervals for maximum plasma concentration and time to achieve maximum plasma concentration were 0.4-0.6 ng·ml -1 and 1.4-3.0 h, respectively. Conclusions: Clonidine nasal drops are erratically absorbed from the nasal mucosa and, thus, this mode of drug administration is not recommended for premedication purposes. © 2008 The Authors

A new and feasible model for predicting operative risk

Background. Although the POSSUM (Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity) score can be used to calculate operative risk, its complexity makes its use unfeasible in the immediate clinical setting. The aim of this study was to create a new model, based on ASA status, to predict mortality. Methods. Data were collected in two hospitals. All types of surgery were included except for cardiac surgery and Caesarean delivery. Age, sex and preoperative information, including the presence of cardiocirculatory and/or lung disease, renal failure, diabetes mellitus, hepatic disease, cancer, Glasgow Coma Score, ASA grade, surgical diagnosis, severity of the procedure and type of surgery (elective, urgent or emergency), were recorded for each patient. The model was developed using a data set incorporating data from 1936 surgical patients, and validated using data from a further 1849 patients. Forward stepwise logistic regression was used to build the model. Goodness of fit was examined using the Hosmer-Lemeshow test and receiver operating characteristic (ROC) curve analyses were performed on both data sets to test calibration and discrimination. In the validation data set, the new model was compared with POSSUM and P-POSSUM for both calibration and discrimination, and with ASA alone to compare discrimination. Results. The following variables were included in the new model: ASA status, age, type of surgery (elective, urgent, emergency) and degree of surgery (minor, moderate or major). Calibration and discrimination of the new model were good in both development and validation data sets. This new model was better calibrated in the validation data set (Hosmer-Lemeshow goodness-of-fit test: chi(2)=6.8017, P=0.7440) than either P-POSSUM (chi(2)=14.4643, P=0.1528) or POSSUM, which was not calibrated (chi(2)=31.8147, P=0.0004). POSSUM and P-POSSUM had better discrimination than the new model, although this was not statistically significant. Comparing the two ROC curves, the new model had better discrimination than ASA alone (difference between areas, 0.077, se 0.034, 95% confidence interval 0.012-0.143, P=0.021). Conclusions. This new, ASA status-based model is simple to use and can be performed routinely in the operating room to predict operative risk for both elective and emergency surgery

Goal-directed Intraoperative therapy reduces morbidity and length of hospital stay in high-risk surgical patients

Abstract: Background: Postoperative organ failures commonly occur after major abdominal surgery, increasing the utilization of resources and costs of care. Tissue hypoxia is a key trigger of organ dysfunction. A therapeutic strategy designed to detect and reverse tissue hypoxia, as diagnosed by an increase of oxygen extraction (0,ER) over a predefined threshold, could decrease the incidence of organ failures. The primary aim of this study was to compare the number of patients with postoperative organ failure and length of hospital stay between those randomized to conventional vs a protocolized strategy designed to maintain O2ER < 27%. Methods: A prospective, randomized, controlled trial was performed in nine hospitals in Italy. One hundred thirty-five high-risk patients scheduled for major abdominal surgery were randomized in two groups. All patients were managed to achieve standard goals: mean arterial pressure > 80 mm Hg and urinary output > 0.5 mL/kg/h. The patients of the "pr..